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Eight Year Follow-Up Shows Safety/Efficacy of Cholesterol-Lowering Pravastatin

An eight year follow-up of pravastatin treatment has shown sustained treatment benefits and safety for patients with previous acute coronary syndromes and average cholesterol concentrations.

These findings reinforce the importance of long-term cholesterol-lowering treatment for almost all patients with previous coronary heart disease events, declares lead author Dr John Simes of the Clinical Trials Center, University of Sydney, Sydney, Australia.

The recommendation is based on the original Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, a randomised placebo-controlled trial undertaken at 87 centers in Australia and New Zealand. The study involved 9,014 patients who had had an acute myocardial infarction, or a hospital discharge diagnosis of unstable angina pectoris three to 36 months before study entry, and whose total cholesterol concentration was 4.0-7.0 mmol/L.

Patients were randomly assigned pravastatin 40 mg per day or placebo, in addition to their usual treatment and dietary advice. The patient's own physician provided usual care during the study.

The clinicians point out that their study and two other large-scale trials - the Scandinavian Simvastatin Survival Study (4S), and the Cholesterol and Recurrent Events (CARE) study - suggested a possible lag in the treatment effect of one to two years after treatment begins. The LIPID trial was stopped early in 1997 because of clear evidence benefit from pravastatin treatment.

However, these researchers felt there was little evidence about the long-term effectiveness or safety of HMG-CoA reductase inhibitors after more than five or six years treatment. This prompted the LIPID investigators to offer all patients pravastatin therapy so they could assess outcomes and safety over at least another two years.

Overall, 7,680 patients (97 percent of those still alive) had two years of extended follow-up, with 3,766 patients (86 percent) of those assigned placebo and 3, 914 patients (88 percent) assigned pravastatin agreed to take open-label pravastatin.

The clinicians found that patients originally assigned pravastatin had almost identical cholesterol concentrations to those assigned placebo, but a lower risk of death from all causes: 219 (5.6 percent) in the pravastatin group compared with 255 (6.8 percent) in the placebo group. The rates for CHD death were 108 (2.8 percent) in the pravastatin group compared with 137 (3.6 percent in the placebo group.

Over the total eight year period, all-cause mortality was 888 (19.7 percent) in the group originally assigned placebo, and 717 (15.9 percent) in the group originally assigned pravastatin. Dr Simes also found stronger evidence of separate treatment benefits in pre-specified subgroups, such as women, patients aged 70, and patients with total cholesterol <5.5 mmol/L.

The absolute risk reduction has increased, suggesting that the cost-effectiveness of pravastatin in secondary prevention is also better than previously estimated.

With more than 1,000 cancers were diagnosed among patients in 9.4 years, "the observed incidence of cancer in the patients originally assigned pravastatin is reassuringly lower than the rate among those originally assigned placebo. To obtain further evidence of long-term safety, we plan to continue to follow up all patients by way of a questionnaire, telephone calls, and health registries for at least a further three years."

Dr Simes and colleagues conclude: "Strategies that can increase the use of cholesterol-lowering treatment among patients with CHD continue to be as important to the reduction of the global burden of cardiovascular disease as the discovery of new treatments.

Assuming there were at least two million deaths from cardiovascular disease worldwide each year, which were potentially preventable by the greater use of lipid-lowering therapy, the treatment of an extra 25 percent of these patients could save more than 100,000 lives each year."
Lancet 2002; 359: 1379-87. "Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up"

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